Gene targeting by homologous recombination can be used to activate or inactivate cellular genes in eukaryotic cells. The objective of this project is to alter the functional status of genes that control growth and maturation of specific tissues and study the biological consequences of these molecularly defined alterations. The tumor growth factor beta (TGF-beta) has been chosen for this study as it is a well-characterized gene whose biological functions are well known. The biological importance of the TGF-beta gene will be studied in the context of a whole organism by targeting a defective gene to its cognate counterpart in embryonic stem (ES) cells by homologous recombination. These cells will subsequently be used to generate transgenic mice containing a defective TGF beta 1 gene. The TGFbeta l gene has been targeted in ES cells. Six targeted clones have been generated and four of these have been used to generate chimeric mice. Two of the clones could generate germ-line chimeras. The offspring of these chimeras carry a mutated TGF beta 1 gene. These heterozygous mice are normal and have been mated to yield mice homozygous for the null TGF beta 1 allele. Two homozygous mice have been born. They are runted, have difficulty opening their eyelids, and die at 3 weeks. Study of this pathological condition is in progress.